Research Location: Simon Fraser University

Novel retinal biomarkers for Alzheimer’s disease

Dr. Faisal Beg is one of five BC researchers supported through the British Columbia Alzheimer’s Research Award. Established in 2013 by the Michael Smith Foundation for Health Research (MSFHR), Genome British Columbia (Genome BC), The Pacific Alzheimer Research Foundation (PARF) and Brain Canada, the goal of the $7.5 million fund is to discover the causes of and seek innovative treatments for Alzheimer’s disease and related dementias.

 

Millions of people worldwide are afflicted with Alzheimer’s disease (AD). In the absence of a complete understanding of the disease, therapeutic trials have been unsuccessful and there remains no cure. Detecting the onset of AD is difficult as the changes in behavior are subtle and hidden. Biomarkers that can reliably detect AD at the earliest possible stage are essential for disease monitoring and treatment to improve the quality of life for patients.

 

Imaging shows that the brain has a protein called amyloid, which accumulates beyond normal amounts in AD. However, brain imaging exams for amyloid are expensive, can be invasive, and not easily available, and as a result, cannot be used for general screening. Studies suggest that amyloid also accumulates in the retina of individuals with AD, but this has not been proven.

 

Dr. Faisal Beg, a biomedical engineer and professor in the School of Engineering Science at Simon Fraser University (SFU), is leading a multi-disciplinary team of researchers from SFU, the University of British Columbia (UBC) and McGill University to find the connection between the eye and AD by investigating it as a potential source for the earliest biomarkers for the disease.

 

The team is developing computational tools and image processing technologies to examine chemical biomarkers, structural degradation, and functional loss in the eye that may be associated with AD. This work could be the basis for a new retina imaging device using laser light that can show the presence of amyloid in the retina. The technology would improve understanding of the disease mechanisms underlying the accumulation and serve as an early indication that the protein is also accumulating in the brain.

 

Beg’s research could lead to an inexpensive, non-invasive retina exam for use in clinics to screen everyone on a regular basis for the earliest signs of amyloid. Besides having the potential to aid in the early diagnosis of the disease, the imaging techniques may also be able to track the progression of AD and assess the efficacy of treatments under development.

 

Cellular resolution OCT for clinical ophthalmology

Two of the leading causes of irreversible vision loss in developed countries are age-related macular degeneration (AMD) and diabetic retinopathy (DR). These diseases lead to the death of photoreceptors, the light-sensitive cells in the retina located at the back of the eye.

Treatments are currently available for “wet” AMD and DR, but there are currently no effective treatments for “dry” AMD. The key to preserving sight is early diagnosis, and monitoring the effects of the novel therapies in development.

The current technologies for non-invasive retinal imaging systems include flood illumination fundus photography, confocal scanning laser ophthalmoscopy (SLO) and optical coherence tomography (OCT). The resolution attainable with these techniques doesn’t permit visualization of the photoreceptor mosaic. The limiting factor to this ability is the eyes themselves—the cornea and lens that focus light onto the retina do not have microscopic abilities.

Dr. Sarunic has developed a novel instrument combining wavefront sensorless adaptive optics (SA) with OCT to correct ocular aberrations. This novel SAO OCT can achieve cellular resolution imaging of the retina, visualizing the individual photoreceptors that form a mosaic pattern on the retina (akin to looking at the pixels in a camera). This SAO OCT design is compact and clinically friendly, and with further investigation and commercialization, could lead to improved diagnosis and treatment for those with vision loss.

An advanced wearable robotic exoskeleton for assisting people with lower limb disabilities

Human locomotion is influenced by many factors, including neuromuscular and joint disorders that affect the functionality of joints and can cause partial or complete paralysis. Reduced mobility is estimated to affect over 1.5 million people in the United States alone. Many individuals require mobility assistive technologies to keep up with their daily life, and the demand for these devices increases with age.

 

A wearable robotic exoskeleton is an external structural mechanism with joints and links corresponding to those of a human body. It is synchronized with the motion of a human body to enhance or support natural body movements. The exoskeleton transmits torques through links to the human joints and augments human strength.

 

Dr. Arzanpour has developed a novel wearable robotic exoskeleton for assisting people with lower limb disabilities, such as spinal cord injury patients. The robot is highly versatile and capable of guiding the lower limb joints to perform all normal and complex movements. The technology is light, modular, portable, programmable and relatively inexpensive, and is particularly innovative in its versatile hip, knee and ankle joint mechanism, such that the normal range of motion of the natural joints is preserved.
Human in Motion has recently completed XoMotion-R, the world’s most advanced rehabilitation exoskeleton.  XoMotion-R has received its first regulatory approval, clearing the way for it to be marketed and sold in Canada. Set to revolutionize ambulatory training in rehabilitation facilities, XoMotion-R is designed to aid patients with spinal cord injuries (SCI), stroke, and other neurological conditions by providing unparalleled support with its self-balancing and hands-free functionality.

 

End of Award Update – October 2024

 

Results

This project was focused on R&D development and testing of our next-generation exoskeleton system. We initially went through several rounds of prototyping and improving the robot. The prototypes were internally tested, and improvements were made from the feedback we received. As a result, we completed the product design and are currently assembling the units to conduct our clinical studies for FDA approval. We also went through multiple rounds of financing from private investors. In August, we received our Health Canada approval, which is our first regulatory approval. This will allow us to start our sales in Canada and we are very excited about that.

 

Impact

 

Motion disability drastically reduces the quality of life for millions of people who are affected and their families. Currently, 17 million people in the US have serious difficulty walking less than a quarter mile a day. That includes 3.3 million who are unable to stand up and walk. The impact of comorbidity complications of motion disability, such as obesity, low employment rate, mental health, and secondary health complications, have an even greater impact on people’s lives and society. Every hour, 320 new cases of Traumatic brain injury, 90 new cases of stroke, and 2 cases of spinal cord injury happen in the US alone. Some of them with severe injuries lose their walking ability forever and must rely on a wheelchair for all their mobility needs. Others with milder injuries can regain their mobility through outcome-based rigorous rehabilitation therapy.

 

Human in Motion Robotics Inc. (HMR) has designed the next generation of exoskeleton systems (a wearable robotic suit) to (i) enable completely paralyzed individuals to walk freely, naturally and independently, and (ii) maximize the outcome of physical therapy and revolutionize the standard of care in rehabilitation. The currently available exoskeletons in the market can only walk forward. Users must balance their weight and the robot’s weight using arm crutches. They must be accompanied by others to assist them with balancing and all other motions that the robot can not support. Therefore, these robots can neither meet the mobility needs of fully disabled individuals nor the comprehensive, safe, and objective needs of rehabilitation. HMR exoskeleton has filled the functionality gap of the existing robots and addressed the needs of both groups.

 

Potential Influence

Our revolutionary exoskeleton articulates all the motions that are needed for complex maneuvers such as forward, backward, and sideways walking (multiple speeds), turning, change of direction, steps, slopes, and crouching. With this unique capability, our intelligent motion generation algorithm can create stable human-like gaits without the need for arm crutches and human attendants. This ground-breaking technology has integrated hardware design excellence with intelligent software algorithm innovation to create a versatile wearable robotic masterpiece with applications above and beyond physical rehabilitation and mobility. Our vision is to offer this disruptive wearable robotic solutions to empower all humans to tackle challenges beyond their physical capabilities.

 

Next Steps

We are currently focused on conducting clinical studies to get FDA clearance for several indications, including spinal cord injury and stroke. The FDA clinical studies are mainly focused on device functionality and safety. Further clinical studies are needed to demonstrate efficacy and establish best practice protocols based on long-term therapy outcomes. We are currently meeting with potential national and international partners interested in collaborating with us to conduct studies in their centers.

 

Neuromodulation research program for youth addiction and mental health

Each year, approximately 1 in 5 Canadians experiences a mental health or addiction problem. Young people aged 15 to 24 are more likely to experience mental illness and substance use than other age groups.

Depression is one of the most common mental illness, but current treatments are either ineffective or lead to side effects in up to 50% of youth. In youth, medications are often borrowed from adult population not accounting for age-related brain differences. New solutions are needed to address major gaps in treatment of youth mental health.

Dr. Farzan is collaborating with physicians, neuroscientists, engineers, and health authorities to develop and apply more precise and innovative methodologies to study the brain and address this gap. She is combining non-invasive brain stimulation and brain monitoring technologies to study what may underlie depression in young age, and how each treatment affects the brain. She is also developing non-invasive brain stimulation technologies for youth that do not respond to medications or behavioral therapy. This research has tremendous potentials for leading to introduction of a new therapy for youth who are failing currently available treatments.

Orthogonal multicolour high-affinity tags for RNA imaging and manipulation

RNA plays a very important role in the regulation of gene expression. Yet, the spatial and temporal dynamics of RNA are still poorly understood, mainly due to the scarcity of effective and simple RNA imaging and purification techniques.

The development of technologies that simultaneously allow imaging, purification and manipulation of multiple RNAs in live cells promises to enable the study of RNA in development, metabolism and disease, which is essential for understanding the control of gene expression in diseases such as autism, cancers and type II diabetes.

Dr. Dolgosheina will develop a multicolour RNA-based imaging method that will allow researchers to simultaneously visualize two RNAs in living cells, while concurrently purifying and/or manipulating RNA interactions with other biomolecules. This new technology will build on, and dramatically increase the capabilities of the bright, high affinity RNA Mango system that she developed during her PhD.

The proposed project is working on an outstanding international problem, and since these tools are urgently needed, the research has attracted significant national and international attention.

This research project will 1) result in international level talks and publications, 2) bring together some of the best international researchers in RNA biophysics and 3) result in intellectual property development, industrial research and training and commercialization via a rapidly growing Canadian biotechnology company, Applied Biological Materials (Richmond, BC).

Novel 18F-fluorinated amino acids as oncological PET radiotracers

Positron emission tomography (PET) is a non-invasive imaging technique used to detect tumours and provide information about a patient’s response to treatment. PET generates a 3D image of the inside of a patient’s body and highlights the location of tumors through detection of a radiotracer administered before generating the image. One of the most common forms of radiotracers are small, drug-like molecules containing a radioisotope that bind to or accumulate in cancer cells, precisely locating tumours. 

While many radioisotopes can be used for PET imaging, [18F] is arguably the most desirable due to its high positron output, small atomic size, metabolic stability and worldwide network of production facilities. Despite these advantages, the synthesis of [18F] radiotracers presents many challenges that have limited the scope of radiotracers available for oncological PET imaging. Thus, the majority of oncological PET imaging relies on a single radiotracer: [18F]-FDG, a sugar analogue that preferentially accumulates in cells that have increased metabolism (i.e., cancer cells). 

Unfortunately, [18F]-FDG is not cancer-specific and also tends to bind to other tissues such as brain and bladder, and at sites of inflammation, limiting its utility for detecting tumors in those areas. In recent years there has been considerable interest in identifying complementary radiotracers to FDG, and much attention has focused on the synthesis of 18F-labelled amino acids, which also accumulate in rapidly dividing cancer cells. Dr. Britton’s lab has recently discovered a method for incorporating the [18F] radioisotope into complex drug precursors without the need for elaborate precursor synthesis. 

Dr. Britton aims to:

  • Rapidly expand the number of available amino acid radiotracers using new unique capabilities.
  • Evaluate promising lead radiotracers for oncological PET imaging.
  • Advance selected radiotracers into preclinical animal studies.

In addition to these research aims, Dr. Britton has filed a provisional patent application and will work with the SFU Innovation Office to identify an industrial partner for this new technology. These new amino acid radiotracers could have a profound impact on the early detection of cancer and positively impact the lives of many British Columbians.

Elucidating the effect of O-GlcNAc modification on protein stability

The glycosylation of proteins with O-GlcNAc is a ubiquitous post-translational modification found throughout the metazoans. Deregulation of O-GlcNAcylation is implicated in several human diseases including type II diabetes, Alzheimer’s disease, and cancer.

 

However, the basic biochemical roles of O-GlcNAcylation remain largely unanswered. Several recent studies have demonstrated a clear link between O-GlcNAc and cellular thermotolerance.

 

It is likely that a basic function of the O-GlcNAc modification prevents the unfolding or aggregation of target proteins. Dr. King will investigate its role in protein stability through series of biochemical and biophysical experiments to probe the effect of O-GlcNAc on protein unfolding, folding, and aggregation. The results of this research will provide important insights into the basic molecular mechanisms governing O-GlcNAc deregulation in human disease.

 

End of Award Update: July 2022

 

Most exciting outputs

The modification of proteins by O-linked N-acetylglucosamine (O-GlcNAc) is a widespread post-translational modification (PTM) that is dysregulated in several human diseases including type II diabetes, Alzheimer’s disease and cancer. However, research progress in this area is hampered by the fact that it is challenging to detect O-GlcNAc on proteins. Further, the basic biochemical roles of O-GlcNAcylation remain largely unanswered.

 

Therefore, we developed a mass spectrometry based method to precisely map sites of O-GlcNAc on proteins. This method employs a UV laser to produce a diversity of O-GlcNAc retained fragment ions, enabling mapping protein modification sites with unprecedented precision.

 

We then explored the role of O-GlcNAc as a biochemical regulator of protein stability. We developed a new high-throughput approach to profile the effect of O-GlcNAc on the thermostability of the proteome. Using this method, we identify several proteins that are regulated by O-GlcNAc. Interestingly, the majority of these proteins display an O-GlcNAc dependent decrease in stability, challenging the prevailing view of O-GlcNAc as being a predominantly stabilizing modification. Thus, we show that O-GlcNAc is a bi-directional regulator of protein stability. We deliver a powerful approach that provides a blueprint for determining the impact of, in principle, any PTM on the thermostability of thousands of proteins in parallel.

 

Impacts so far
This work delivers powerful tools for exploring the role of O-GlcNAc and other labile PTMs as regulators of protein biochemistry.

 

Potential future influence
Decreased levels of protein O-GlcNAcylation is associated with Alzheimer’s disease. However, the basic biochemical mechanisms underlying this association remain unknown. Here we show that O-GlcNAc regulates the stability of several proteins within human cells, a phenomenon that may impact cellular protein levels in Alzheimer’s disease. This fundamental research is important for understanding the impact O-GlcNAc has on protein structure and stability, particularly in the context of its dysregulation in neurodegenerative disorders.

 

Next steps
We plan to continue exploring the influence O-GlcNAc has on protein structure and function. In doing so, we hope to improve our understanding of the fundamental mechanisms underlying neurodegeneration. This research may ultimately provide knowledge that contributes toward the development of new therapeutic strategies.

 

Useful links

Development of improved substrates for live cell imaging to aid in discovering new glucocerebrosidase therapeutic agents

Parkinson’s disease (PD) is a neurodegenerative disorder that affects millions of people worldwide, with no standard treatment currently available. Therefore, there is a major need for new therapeutic agents to treat or prevent the progression of PD. One promising solution involves targeting the protein glucocerebrosidase (GCase) encoded by the gene GBA1. Studies have shown small molecules that increase GCase activity could help prevent the progression of PD.

Dr. Ashmus will use a combination of organic chemistry, chemical biology, and cell biology to discover new therapeutic agents that increase GCase activity. Fluorescently-quenched substrates will be chemically synthesized and used in enzymatic assays to monitor GCase activity in vitro and in neuroblastoma cells. The assay will then be adapted and optimized for use in a high-throughput screen of compounds from the Canadian Glycomics Network and from a natural products collaborator, Roger Linington, at SFU.

The results of this research could produce new lead compounds that increase GCase activity. In addition, the compound screen could aid in identifying new therapeutic targets for PD, which would drive preclinical translation research in this area.

End of Award Update – March 2022

Most exciting outputs

An exciting and successful specific output as part of the project was that we were able to develop a newly designed probe that performs better than the original probe the Vocadlo Lab published and patented back in 2015. The new probe is also capable of being used in a high-throughput screening in live cells. Moreover, the new design led to the development of probes that could for the first-time target other disease-related enzymes of interest in live cells and led to a high-impact publication in Nature Chemical Biology.

Impacts so far

While the main purpose of the research project failed to discover any lead compounds that could be developed as a potential therapeutic agent for Gaucher/Parkinson’s disease, the steps (develop a better probe and optimize use for screening) required to reach the point of running the screen were successful. The data collected (unpublished) has helped secure funding for the Vocadlo Lab and led to collaborations with biotech companies interested in targeting the same enzyme.

Potential future influence

I think some of the work described briefly will start to gain more attention in the next few years. Over the past year or so, I have noticed an increased interest from research institutes and biotech companies in studying enzymes found within the lysosome. This is in part because more of these lysosomal enzymes are being linked to neurological diseases so having biochemical tools that can study them in live cells will be desired. I think some of the probes we have developed over the past couple of years will be of interest to a broader scientific community.

Next steps

The work searching for potential therapeutic agents for Gaucher/Parkinson’s disease is currently ongoing. The majority of my research efforts have shifted to developing and evaluating novel probes targeting other disease-related enzymes. One notable example is a new project collaborating with an expert clinician in Fabry’s Disease. Using one of our recently developed probes, we aim to advance current diagnostic methods and improve dosing and timing of current therapeutics for Fabry Disease patients. I am excited to see some of my work being used in a clinical setting and hope this can lead to something more fruitful in time. Dissemination of the work will be continued through publications, presentations at conferences and through social media platforms.

Useful links

Development of a flow cytometry assay for accurate and selective measurement of lysosomal GBA1 activity in PBMC

Recently, loss-of-function mutations of the GBA1 gene, which encodes glucocerebrosidase (GCase), have been characterized as a major genetic risk for Parkinson’s disease (PD). Patients carrying these mutations have a much higher incidence of PD, earlier onset, and more severe disease.

These data strongly suggest that GCase activity may be useful for early diagnosis as well as monitoring the progression of PD. Dr. Gros will build on her previous work describing a substrate that specifically measures GCase activity both in vitro and in neuronal cells in microscopy. This research will lead into a proof-of-concept clinical study, using a flow cytometry assay to establish correlations between the progression of PD, GBA1 mutant status and GCase activity.

The results of this study will lead to the development of a new assay for clinical studies that will benefit Parkinson’s patients and deepen our overall understanding of the disease.

 

Studying genetic mechanisms of treatment resistance in non-Hodgkin lymphomas

Dr. Morin's research program will develop and apply laboratory and computational genomic methodologies that use DNA sequencing and other sensitive platforms to study the drivers of tumour onset, progression and treatment resistance in solid cancers in order to understand the somatic drivers of non-Hodgkin lymphomas (NHLs). Using massively parallel (next-generation) DNA and RNA sequencing, Dr. Morin will be able to identify somatic alterations and gene expression signatures in tumour tissue and liquid biopsies (circulating tumour DNA). To properly study such large data sets, he will utilize cutting-edge bioinformatics techniques and develop novel analytical approaches and pipelines that will allow leverage of unique sample processing techniques and applications.

Moving forward, this research will investigate aggressive subtypes of NHL including patients who typically fail standard-of-care treatments. Dr. Morin will rely on features of this malignancy such as high somatic point mutation rate, a well established list of known lymphoma-related genes, and the presence of clonal immunoglobulin rearrangements to develop assays to study the genetics of specimens from NHL patients in various ways. These include deep sequencing using a novel molecular barcoding system and digital PCR-based methods. He will continue to push the limits of sequencing technology by applying deep sequencing and whole exome sequencing to circulating tumour DNA. Under this research program, he will also continue to use a variety of laboratory and computational approaches to understand the clonal structure of NHLs, especially in the context of serial samples collected over the course of disease progression and after treatment failure or relapse. 

Dr. Morin's lab, along with the BC Cancer Agency, plan to pursue options to commercialize these strategies so that a broader group of users can use these techniques for research and clinical applications. Some of the research under this program will involve evaluating the performance of novel ctDNA-based methods to study tumour genetics and evaluate treatment responsiveness. This will be conducted in the context of prospective and retrospective samples from multi-centre clinical trials in Canada. This engagement with clinicians and publications describing these trials will help accelerate the adoption of such emerging technologies to the clinic.